Sepsis

last authored: Sept 2013, David LaPierre
last reviewed:

 

 

 

Introduction

Sepsis represents a life-threatening infection accompanied by a systemic inflammatory response syndrome (SIRS). It is a significant cause for illness and death, especially of hospitalized patients, with mortality rates at 25% for severe sepsis and 50% for septic shock.

 

Systemic bacterial infection may be classified according to increasing severity:

sepsis: SIRS with proven infection

severe sepsis: sepsis with organ dysfunction or a lactate >4

septic shock: persistent hypotension, despite IV fluids, and evidence of organ hypoperfusion

 

Rates of sepsis, and sepsis-related deaths, have increased dramatically, as populations age and chronic disease rates continue to climb. There is now an incidence of 3/1000 people in North America, or 2/100 hospitalized patients. It is now the 13th most common cause of death in the US, with approximately 750,000 cases per year.

 

 

 

The Case of Ms d'Souza

Ms d'Souza is a 64 year-old woman who was recently discharged from hospital after a one week admission for cellulitis. Once at home, she developed shortness of breath and returned to the emergency department. There, she was febrile, with a heart rate of 120, blood pressure of 86/56, and respiratory rate of 38.

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Causes and Risk Factors

Sepsis is principally caused by bacterial infections, though viral, fungal (ie Candida), rickettsial, mycobacterial, or parasitic infections. Common bacterial pathogens include:

Gram-positive bacteria

  • Staphylococcus aureus
  • coagulase negative Staphylococcus
  • Streptococcus
  • Enterococcus

Gram-negative bacteria

  • E. coli
  • Klebsiella
  • Proteus
  • Pseudomonas
  • Anaerobes
  

 

Sepsis can begin following a variety of infections, including:

 

Risk factors for the development of sepsis include:

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Pathophysiology

main articles: inflammation     coagulation

SIRS leads to endothelial disruption and microcirculation defects, with subsequent tissue hypoxia.

 

Sepsis is caused by the body's response to pathogens, commonly triggered by bacterial products such as LPS, endotoxin, teichoic acid, or peptidoglycan. These products are taken up by macrophages, who respond by producing large amounts of pro-inflammatory cytokines such as TNF, IL-1, IL-6, IL-8, and G-CSF. Cytokines have multiple actions, inducing systemic response as well as stimulating T cells, B cells, and NK cells.

 

Direct bacterial action, along with inflammation, leads to endothelial damage and disruption of blow flow through the capillaries. This leads to reduced blood flow, impaired oxygenation, and organ damage. Anaerobic metabolism leads to increased lactic acid production.

 

Coagulation can be induced by TNF and other pro-inflammatory cytokines, tissue factor release, both through intrinsic and extrinsic pathways. Anticoagulants become depleted, further inducing blot clot. Endotoxin stimulates membrane phospholipid production of platelet-activating factor (PAF), prostaglandins, and leukotrienes.

Resulting widespread microvascular thrombosis can act with disseminated intravascular coagulation to induce ischemia (lactate) and mulitple organ failure. DIC occurs in 2-3% of patients.

 

Hormones such as cortisol, glucagon, and epinephrine can also be produced in response to endotoxin.

 

Profound activation of the immune response during the early stages of sepsis can lead to depletion of cells and their mediators, causing significant immunosuppression. Alongside this, a strong, sustained anti-inflammatory response leads to immunoparalysis. In this case patients normally survive the initial septic event, but are at high risk of dying from further septic challenges.

This immunoparalysis can last days to weeks, and the threats can be relatively innocuous.

 

Within the heart, vasodilation leads to decreased venous return. Increased ventricular compliance leads to poorer contractility and decreased cardiac output.

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Signs and Symptoms

  • history
  • physical exam

History

Patients often describe abrupt onset of systemic symptoms such as:

  • fever
  • chills and rigors
  • malaise/myalgias
  • altered mental status

Specific sites of infection can lead to specific symptoms:

  • respiratory - cough, shortness of breath, chest pain
  • urinary - pain, increased frequency or urgency, flank pain
  • abdominal - pain, nausea, vomiting, diarrhea
  • nervous system - headache, photophobia, neurologic dysfunction, neck stiffness

Assess underlying diseases, previous infections and antimicrobial therapy, and symptoms of local infection.

Inquire into travel, occupational exposure, or encounters with infectious sources.

Physical Exam

Most patients have fever, though a small percentage of patients may be hypothermic (<36.4 C). Fever is less likely in the elderly and those with renal or liver failure.

Signs of sepsis are non-specific. They include:

  • tachycardia
  • tachypnea and respiratory alkalosis (early sign)
  • fever
  • hypothermia (poor prognosis)
  • hypotension
  • mental status changes or delirium
  • cyanosis, jaundice, skin mottling
  • petechiae, purpura
  • embolic lesions
  • ecthyma gangrenosum (especially gram negative bacteria)

Central venous pressure (CVP) is derived from subclavian or internal jugular lines.

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Investigations

  • lab investigations
  • diagnostic imaging

Lab Investigations

In a patient with suspected sepsis, rapid bloodwork is necessary. Investigations to order include:

  • CBC (neutrophilia with left shift; neutropenia is common in severe infections, alcoholics, and the elderly)
  • electrolytes
  • creatinine, BUN
  • glucose (may be quite elevated in the absence of DM)
  • liver enzymes
  • INR, PTT (abnormal coagulation may be present)
  • lactic acid
  • arterial blood gas (hypoxemia, respiratory alkalosis)
  • troponin
  • urinalysis (proteinuria)

Blood cultures should be drawn from two or three different sites before beginning antibiotic therapy. Optimally sampled cultures have a sensitivity of >95%. The false negative rate for a single culture of 5-10 ml is 30%.

Two or three sets of blood cultures have a sensitivity of 89% and 99%, respectively, in people with bacteremia.

 

 

Obtain cultures or swabs from other potential sites, ie urine, sputum, wounds.

 

Central venous saturation: measured from the central line. Should normally 65-70%; if tissue demand is poor, this will result in decreased saturation.

Diagnostic Imaging

Chest X ray, abdominal ultrasound, and CT/MRI should be done to assess potential sites of infection, as directed by history and physical exam.

ECG may be done to rule out a cardiac cause of the presentation.

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Differential Diagnosis

SIRS can occur with pancreatitis, trauma, burns, or other causes.

 

The differential diagnosis for a presentation suggestive of sepsis includes:

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Treatments

Early recognition of sepsis and initiation of treatment is of paramount importance. Patients are best served in the ICU, especially if hypotensive. Treatment should be multi-pronged, and unstable patients should be monitored.

 

Provide supplementary oxygen and secure the airway as necessary.

 

Obtain peripheral and central venous access. Fluid resuscitation should be agressive, using 20ml/kg or 1-2 L of crystalloid.

 

Early goal-directed therapy (EGDT) (Rivers et al, 2001) suggests targets for resuscitation over the first six hours:

Vasopressors, including norepinephrine, epinephrine, vasopressin, dopamine, or phenylephrine (second line) may be used to reach targets, especially for MAP.

 

Antibiotics: provide antimicrobial therapy as soon as sepsis is suspected. Ideally, draw blood cultures before antibiotics are given. Use bacteriocidal, intravenous antibiotics as possible, ensuring good tissue penetration. Initially begin with coverage for both gram positive and gram negative bacteria, adjusting as sensitivity suggests. Initial choices depend on institution and patient situation, and include:

Adult, Pseudomonas unlikely

  • vancomycin plus ceftriaxone/cefotaxime
  • pipercillin-tazobactam
  • imipenem/meropenem

 

Adult, Pseudomonas possible

  • vancomycin plus
  • cetftazidime/cefipime
  • pipercillin-tazobactam + ciprofloxacin/gentamycin

 

children

  • cefotaxime

 

neonates

  • ampicillin and gentamycin

Ensure allergies, as well as renal and hepatic function, are considered.

Adjust treatment according to sensitivities, as directed by cultures.

 

Reduce oxygen demand by ie sedating and intubating, to reduce catecholamine drive and the work of breathing.

 

 

remove predisposing factors: stop immunosuppressants if possible.

identify source: remove infected hardware and drain abscesses as appropriate. Use least invasive measures to accomplish this.

 

transfusion of pRBCs (until hematocrit >30%)

sedation and paralysis can assist in reducing metabolic demand.

corticosteroids can be used if hymodynamics cannot be improved, despite effective fluids and pressors.

biologics: blockade of TNF-alpha or IL-1 appears to show promise in reducing shock. Other options include binding endotoxin. Recombinant activated protein C (drotrecogin-alpha) can reduce mortality, but leads to increased risk of bleeding. Research is evaluating IFN-gamma and GM-CSF as agents to address d

diet: Keep patients NPO initially until stable. Maintain serum glucose between 80-100 mg/dl.

 

Due to rates of false negatives, if a patient with a negative culture responds to antibiotics, and in the absence of other explanations, antibiotics should be continued.

 

There are many potential causes of delays in effective treatment (Kumar, 2013):

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Consequences and Course

Patients who are otherwise healthy have a mortality rate of <5%. Those with serious conditions, such as cancer, cirrhosis, or aplastic anemia have a 15-20% chance of mortality, while patients with neutropenia or other immune dysfunction have a 40-60% mortality rate (McPhee and Papadakis, 2008).

Sepsis is more likely to be fatal with the following risk factors:

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Additional Resources

Kumar A 2013.

Rivers E et al. 2001. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM. 345: 1368-77.

Global Sepsis Alliance

 

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Topic Development

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